3G8 is a mouse monoclonal anti Fc receptor antibody which recognizes and blocks the active site of FcRp52-70, an FcR found on granulocytes, tissue macrophages, and large granular lymphocytes. MPS FcR blockade with another mouse monoclonal anti FcR antibody (24G2) has been shown to decrease clearance of immune complexes in mice. Our studies in chimpanzees showed that infusion of 3G8 substantially slowed clearance of opsonized red cells. Clinical studies with intravenous gammaglobulin (IVGG) has suggested that MPS FcR blockade could underlie therapeutic responses in autoimmune thrombocytopenic purpura, a severe bleeding disorder in which profound thrombocytopenia is mediated by opsonization of platelets with antiplatelet antibody. After obtaining and IND, 3G8 was infused into 4 patients with refractory ITP all of whom had platelet counts consistently less than 10,000/ul and significant clinical bleeding. Three of 4 patients demonstrated substantial acute platelet increases to levels of 34,000/ul, 80,000/ul and 300,000/ul; one patient did not respond. Surprisingly, the 3 patients with acute responses also all had long-term benefits lasting months. Two patients continue to maintain adequate platelet counts without any therapy 3 and 10 months after 3G8, the 3rd patient regained responsiveness to IVGG and now requires IVGG treatment only every 5 weeks. Serial opsonized red cell clearances indicated that the acute effects were due to MPS FcR blockade. However the longterm effects could be caused by either prolonged MPS FcR blockade and/or by decreased levels of antiplatelet antibody. MPS FcR function will be studied by serial opsonized red cell clearances. The mechanism of this effect will be explored by studying antiidiotypic and antiantiidiotypic antibody levels. Antiidiotypes were detected in less than 2 weeks in patient #1 and persisted. Development of an antiantiidiotype could mimic the effect of 3G8 and create endogenous modulation of FcRp52-70 expression. Alternatively serial study of antiplatelet antibodies might reveal a decrease that could explain the longterm benefits. If seen , a decrease might occur as a result of the transient ablation of natural killer (NK) cells seen immediately following infusion of 3G8, since NK cells contribute to immunoregulation of immunoglobulin production. 3G8 is a promising new therapy of refractory ITP. Its use in these patients will allow study of FcR immunodulation in autoimmune disease.